p53, NFκB, STAT3, and several other transcription factors are reversibly methylated on lysine residues by enzymes that also modify histones. The methylations of NFκB and STAT3 take place when they are bound to promoters, suggesting a more general model in which the binding of inducible transcription factors to DNA helps to recruit chromatin-modification machinery, which then may modify not only histones but also the bound transcription factors. Mutations of some histone-lysine methyltransferases and demethylases are linked to cancer, and these mutations may alter the methylation not only of histones but also of transcription factors, and thus may be tumorigenic through more than one mechanism. In recent years, much attention has been focused on posttranslational modification of chromatin because of its critical role in regulating gene expression [1]. The N-terminal tails of histones, as well as positions in the globular domains, carry methylations, acetylations, phosphorylations, ADP ribosylations, ubiquitinations, sumoylations, and other modifications [2]. Many different amino acid residues of each of the four core histones have been identified as modification sites [3] and some lysine side chains can be methylated or acetylated alternatively. These modifications provide entry sites for accessory proteins that help to determine higher order chromatin organization, leading to the activation or inactivation of specific genes. The lysine ε-amino groups can receive one, two, or three methyl groups and the extent of lysine methylation at a single lysine residue can be read differently by different effector proteins [4]. H3K4 methylation is associated with an early-elongating form of RNA polymerase II at actively transcribed genes, H3K9 and H3K27 methylation are linked to heterochromatin formation, while H3K36 methylation provides a stable molecular mechanism for establishing chromatin context throughout the genome by distinguishing potential regulatory regions from transcribed chromatin [5]. Moreover, increasing evidence indicates that nonhistone proteins are subject to reversible acetylation or methylation by histone-modifying enzymes. Among these nonhistone targets are transcription factors, hormone receptors, signal transducers, chaperones, and proteins of the cytoskeleton [6][7][8][9][10][11][12]. Although the acetylation of nonhistone proteins has been appreciated for some time [9,13,14], their methylation has been recognized only more recently. Here, we provide a summary of recent work showing lysine methylation of transcription factors that have well-recognized roles in tumorigenesis and of the effects of mutations of lysine methyltransferases and demethylases in cancer, and we cite evidence that at least some modifications take place only on promoter-bound transcription factors.
Lysine methylation of nonhistone proteinsReversible modification of histones by methylation and demethylation, which occur at both lysine and arginine residues, plays an important role in many biological processes, including transcri...